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Researchers
announced today in the journal
Lancet Oncology that they are well on the way to discovering why
women with the faulty genes BRCA1 and BRCA2 develop breast and
ovarian cancer rather than other cancers.

The
study, carried out by researchers at the UCL Department of Women’s Cancer,
found that abnormal levels of female hormones in the bloodstream could be the
answer. The findings have already led to more research into novel ways of
preventing cancer in women at risk.

According
to the results of the study, women with BRCA1
or BRCA2
mutations are exposed to different levels of the female hormones oestradiol and
progesterone, which are already known to be risk-factors for breast and ovarian
cancer.

The
findings indicate that BRCA
carriers have abnormal hormone regulation, possibly due to a mechanism linked
to the altered BRCA
genes in carriers’ ovaries. It is also possible that BRCA gene alterations
change the sensitivity of tissues to hormones. More research into these mechanisms
is needed.

The study opens up a new window of opportunity to prevent breast and ovarian
cancer in BRCA
mutation carriers. The authors anticipate that following further lab work, an
existing drug – currently used to treat osteoporosis – could be suitable for
use in a clinical trial of breast cancer prevention in BRCA1/2 carriers.

Professor
Martin Widschwendter, Head of the UCL Women’s Cancer Department who led the
research said: “We have shown for the first time that cancer risk in BRCA1 and BRCA2 carriers is not just
caused by local defects in the ability of cells to repair themselves.”

We have shown for the first time that cancer risk in BRCA1 and BRCA2 carriers is not just caused by local defects in the ability of cells to repair themselves.

Professor Martin Widschwendter

He
added: “An additional, systemic problem – abnormal levels of female hormones in
the bloodstream and altered downstream effects – is the likely explanation as
to why BRCA1/2
mutations carriers develop breast and ovarian cancer rather than other
cancers.”

In
the study, researchers analysed 1966 uterus lining thickness measurements,
taken using ultrasound scans. They compared 1573 measurements in women negative
for both mutations with 203 measurements from carriers of BRCA1 and 190 with BRCA2.

Because
the thickness of the uterus lining, or endometrium, is known to depend at least
partly on the levels of female hormones, researchers then measured the
concentration of these hormones in the participants’ bloodstreams.

Not
only did they find that carriers of BRCA1/2
did have higher concentrations of female hormones, they also found that
differences in the levels of hormones correlated with the differences in the
thickness of the endometrium in the second half of the menstrual cycle.

Based
on these findings, research has already begun into how estrogens affect the
Fallopian tubes, as this is where the majority of “ovarian” cancers in BRCA1/2 carriers actually
start. The goal is to design drugs that might prevent the carcinogenic effect
of high concentrations of estrogens in the Fallopian tube.

The
other female hormone, progesterone, is known to trigger molecular changes in
breast cells, specifically the production of the growth factor protein RANKL,
which lead to cancer. Blocking and neutralizing RANKL by applying an antibody
is an entire new concept to prevent breast cancer and will be tested in women
with BCRCA1/2
mutations by Prof Widschwendter’s team after further laboratory work.

Dr
Adam Rosenthal, from Barts Cancer Institute and one of the
study co-authors, said: “Many women with BRCA1
or BRCA2
mutations decide to have their breasts and ovaries removed because of their
high-risk status. Clearly this is a drastic measure and there is an urgent need
to develop less extreme approaches for cancer prevention in such women.”

Helena
Morrisey, chairman of The Eve Appeal is delighted with the news. “We are proud
to have funded this research which is a fantastic step towards our ultimate
goal of prevention of women’s cancer. We are hopeful that based on this
study and future work funded by the Eve Appeal, women at high risk won’t have
to go through what Angelina Jolie went through.”

The
research was funded by The Eve Appeal with contributions from the European
Union, Cancer Research UK and the US National Institutes of Health.